ABSTRACT Lung cancer (small cell and Non-Small Cell Lung Cancer [NSCLC]) is the number one cause of cancer death in men and women in the US with more people dying of lung cancer than the combined total from colon, breast and prostate cancer (>150K deaths/year). While newer chemotherapeutic approaches have shown some improvements, ~70% of NSCLC patients escape all of these therapies and succumb to the disease. Consequently, there is a great need to develop novel genetic precision medicine therapeutics that specifically target and kill lung cancer cells based on their oncogenic mutations, while sparing normal cells. siRNA-induced RNA interference (RNAi) responses have great potential to develop truly precision genetic medicines that can target the entire ?undruggable? genome. Indeed, RNAi targeting of the otherwise undruggable KRASMut and cMYC master oncogenes that drive cancer growth and survival can induce a synthetic lethal RNAi response that selectively kills lung cancer cells, while leaving the surrounding normal cells unharmed. Unfortunately, despite its promising therapeutic features, due to their requisite negatively charged phosphate backbone, siRNAs have no ability to enter cells and require a delivery agent. Consequently, siRNA delivery remains the technological problem to solve for development of RNAi therapeutics to treat lung cancer. To tackle the RNAi delivery problem, we pioneered development of a next-generation RNAi trigger, called RiboNucleic Neutral (siRNN) prodrugs. siRNNs represent a ?Prodrug? approach where the negative charge is directly neutralized by a bioreversible phosphotriester chemical group that allows for self-delivery of monomeric RNAi molecules into cells. Once inside cells, thioesterase enzymes only present inside of cells, convert neutral siRNNs into charged siRNAs that induce RNAi responses. Unlike siRNAs, siRNNs have many drug-like properties, including extreme stability, enhanced delivery and synthetic scalability. The goal of this high risk/high gain exploratory R21 proposal is treat preclinical mouse models of lung cancer by developing Antibody-RNAi Conjugates (ARC) that target KRASMut and cMYC oncogenes to induce a synthetic lethal RNAi response in lung cancer cells. To develop ARCs, we will conjugate our next-generation siRNN RNAi precision medicine triggers to antibodies targeting the NaPi2b, which is overexpressed on lung cancer cells. Delivery of RNAi triggers remains the technological problem to solve. Our proposal directly addresses the delivery problem and targets the otherwise undruggable KRASMut and cMYC driver oncogenes.